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2. Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Author

Bohat, Ritu, Liang, Xiaofang, Chen, Yanping, Xu, Chunyu, Zheng, Ningbo, Guerrero, Ashley, Hou, Jiakai, Jaffery, Roshni, Egan, Nicholas A., Li, Yaxi, Tang, Yitao, Unsal, Esra, Robles, Adolfo, Chen, Si, Major, Angela M., Elldakli, Hadil, Chung, Sang-Hyuk, Liang, Han, Hicks, M. John, Du, Yong, Lin, Jamie S., Chen, Xiqun, Mohan, Chandra, and Peng, Weiyi

Published
2024
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3. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Haselimashhadi, Hamed, Mason, Jeremy C, Munoz-Fuentes, Violeta, López-Gómez, Federico, Babalola, Kolawole, Acar, Elif F, Kumar, Vivek, White, Jacqui, Flenniken, Ann M, King, Ruairidh, Straiton, Ewan, Seavitt, John Richard, Gaspero, Angelina, Garza, Arturo, Christianson, Audrey E, Hsu, Chih-Wei, Reynolds, Corey L, Lanza, Denise G, Lorenzo, Isabel, Green, Jennie R, Gallegos, Juan J, Bohat, Ritu, Samaco, Rodney C, Veeraragavan, Surabi, Kim, Jong Kyoung, Miller, Gregor, Fuchs, Helmult, Garrett, Lillian, Becker, Lore, Kang, Yeon Kyung, Clary, David, Cho, Soo Young, Tamura, Masaru, Tanaka, Nobuhiko, Soo, Kyung Dong, Bezginov, Alexandr, About, Ghina Bou, Champy, Marie-France, Vasseur, Laurent, Leblanc, Sophie, Meziane, Hamid, Selloum, Mohammed, Reilly, Patrick T, Spielmann, Nadine, Maier, Holger, Gailus-Durner, Valerie, Sorg, Tania, Hiroshi, Masuya, Yuichi, Obata, Heaney, Jason D, Dickinson, Mary E, Wolfgang, Wurst, Tocchini-Valentini, Glauco P, Lloyd, Kevin C Kent, McKerlie, Colin, Seong, Je Kyung, Yann, Herault, de Angelis, Martin Hrabé, Brown, Steve DM, Smedley, Damian, Flicek, Paul, Mallon, Ann-Marie, Parkinson, Helen, and Meehan, Terrence F

Subjects
Biological Sciences, Genetics, Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software, Mathematical Sciences, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract

MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.ResultsHere we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.Availability and implementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.Supplementary informationSupplementary data are available at Bioinformatics online.

Published
2020

4. Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala

Subjects
Biomedical and Clinical Sciences, Biotechnology, Genetics, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

Published
2019

5. Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, International Mouse Phenotyping Consortium, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala

Subjects
International Mouse Phenotyping Consortium, Genetics
Abstract

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

Published
2019

6. Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Lloyd, KC Kent, Murphy, Christopher J, and Moshiri, Ala

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Eye Disease and Disorders of Vision, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Eye, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.

Published
2018

7. Rapid and Integrative Discovery of Retina Regulatory Molecules

Author

Albrecht, Nicholas E., Alevy, Jonathan, Jiang, Danye, Burger, Courtney A., Liu, Brian I., Li, Fenge, Wang, Julia, Kim, Seon-Young, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gaspero, Angelina, Justice, Monica J., Westenskow, Peter D., Yamamoto, Shinya, Seavitt, John R., Beaudet, Arthur L., Dickinson, Mary E., and Samuel, Melanie A.

Published
2018
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8. FASlprgene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

Author

Bohat, Ritu, primary, Liang, Xiaofang, additional, Chen, Yanping, additional, Xu, Chunyu, additional, Zheng, Ningbo, additional, Guerrero, Ashley, additional, Jaffery, Roshni, additional, Egan, Nicholas A., additional, Robles, Adolfo, additional, Hicks, M. John, additional, Du, Yong, additional, Chen, Xiqun, additional, Mohan, Chandra, additional, and Peng, Weiyi, additional

Published
2023
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10. Abstract 4444: Targeting PI3K isoforms to improve the effectiveness of T cell mediated immunotherapy

Author

Bohat, Ritu, primary, Liang, Xiaofang, additional, Xu, Chunyu, additional, Tang, Yitao, additional, Hou, Jiakai, additional, Egan, Nicholas A., additional, Shi, Leilei, additional, Guerrero, Ashley, additional, Jaffery, Roshni, additional, Burton, Elizabeth M., additional, Liang, Han, additional, Tawbi, Hussein, additional, Davies, Michael A., additional, and Peng, Weiyi, additional

Published
2023
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13. 554 The panorama of tumor intrinsic immune regulators exhibited by genome-wide CRPISR immune screen integrated with comprehensive clinical dataset analysis

Author

Hou, Jiakai, primary, Wang, Yunfei, additional, Shi, Leilei, additional, Chen, Yuan, additional, Xu, Chunyu, additional, Saeedi, Arash, additional, Pan, Ke, additional, Bohat, Ritu, additional, Egan, Nicholas, additional, McKenzie, Jodi, additional, Mbofung, Rina, additional, Williams, Leila, additional, Yang, Zhenhuang, additional, Sun, Ming, additional, Liang, Xiaofang, additional, Ahnert, Jordi Rodon, additional, Varadarajan, Navin, additional, Yee, Cassian, additional, Chen, Yiwen, additional, Hwu, Patrick, additional, and Peng, Weiyi, additional

Published
2021
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14. A resource of targeted mutant mouse lines for 5,061 genes

Author

Birling, Marie-Christine, Yoshiki, Atsushi, Chiani, Francesco, Kaloff, Cornelia, Hörlein, Andreas, Teichmann, Sandy, Tasdemir, Adriane, Krause, Heidi, German, Dorota, Könitzer, Anne, Weber, Sarah, Beig, Joachim, McKay, Matthew, Chin, Hsian-Jean Genie, Bedigian, Richard, Dion, Stephanie, Kutny, Peter, Kelmenson, Jennifer, Perry, Emily, Nguyen-Bresinsky, Dong, Seluke, Audrie, Leach, Timothy, Perkins, Sara, Slater, Amanda, Christou, Skevoulla, Petit, Michaela, Urban, Rachel, Kales, Susan, DaCosta, Michael, McFarland, Michael, Palazola, Rick, Peterson, Kevin A, Svenson, Karen, Braun, Robert E, Taft, Robert, Codner, Gemma F, Rhue, Mark, Garay, Jose, Clary, Dave, Araiza, Renee, Grimsrud, Kristin, Bower, Lynette, Anchell, Nicole L, Jager, Kayla M, Young, Diana L, Dao, Phuong T, DeMayo, Francesco J, Gardiner, Wendy, Bell, Toni, Kenyon, Janet, Stewart, Michelle E, Lynch, Denise, Loeffler, Jorik, Caulder, Adam, Hillier, Rosie, Quwailid, Mohamed M, Zaman, Rumana, Dickinson, Mary E, Santos, Luis, Obata, Yuichi, Iwama, Mizuho, Nakata, Hatsumi, Hashimoto, Tomomi, Kadota, Masayo, Masuya, Hiroshi, Tanaka, Nobuhiko, Miura, Ikuo, Yamada, Ikuko, Doe, Brendan, Furuse, Tamio, Selloum, Mohammed, Jacquot, Sylvie, Ayadi, Abdel, Ali-Hadji, Dalila, Charles, Philippe, Le Marchand, Elise, El Amri, Amal, Kujath, Christelle, Fougerolle, Jean-Victor, Donahue, Leah Rae, Mellul, Peggy, Legeay, Sandrine, Vasseur, Laurent, Moro, Anne-Isabelle, Lorentz, Romain, Schaeffer, Laurence, Dreyer, Dominique, Erbs, Valérie, Eisenmann, Benjamin, Rossi, Giovanni, Fray, Martin D, Luppi, Laurence, Mertz, Annelyse, Jeanblanc, Amélie, Grau, Evelyn, Sinclair, Caroline, Brown, Ellen, Kundi, Helen, Madich, Alla, Woods, Mike, Pearson, Laila, Gambadoro, Alessia, Mayhew, Danielle, Griggs, Nicola, Houghton, Richard, Bussell, James, Ingle, Catherine, Valentini, Sara, Gleeson, Diane, Sethi, Debarati, Bayzetinova, Tanya, Burvill, Jonathan, Adams, David J, Gao, Xiang, Habib, Bishoy, Weavers, Lauren, Maswood, Ryea, Miklejewska, Evelina, Cook, Ross, Platte, Radka, Price, Stacey, Vyas, Sapna, Collinson, Adam, Hardy, Matt, Gertsenstein, Marina, Dalvi, Priya, Iyer, Vivek, West, Tony, Thomas, Mark, Mujica, Alejandro, Sins, Elodie, Barrett, Daniel, Dobbie, Michael, Grobler, Anne, Loots, Glaudina, Gomez-Segura, Alba, Hayeshi, Rose, Scholtz, Liezl-Marie, Bester, Cor, Pheiffer, Wihan, Venter, Kobus, Bosch, Fatima, Goodwin, Leslie O, Heaney, Jason D, Hérault, Yann, de Angelis, Martin Hrabě, Jiang, Si-Tse, Justice, Monica J, Kasparek, Petr, Ayabe, Shinya, King, Ruairidh E, Kühn, Ralf, Lee, Ho, Lee, Youngik, Liu, Zhiwei, Lloyd, K C Kent, Lorenzo, Isabel, Mallon, Ann-Marie, McKerlie, Colin, Meehan, Terrence F, Beaudet, Arthur L, Fuentes, Violeta Munoz, Newman, Stuart, Nutter, Lauryl M J, Oh, Goo Taeg, Pavlovic, Guillaume, Ramirez-Solis, Ramiro, Rosen, Barry, Ryder, Edward J, Santos, Luis A, Schick, Joel, Bottomley, Joanna, Seavitt, John R, Sedlacek, Radislav, Seisenberger, Claudia, Seong, Je Kyung, Skarnes, William C, Sorg, Tania, Steel, Karen P, Tamura, Masaru, Tocchini-Valentini, Glauco P, Wang, Chi-Kuang Leo, Bradley, Allan, Wardle-Jones, Hannah, Wattenhofer-Donzé, Marie, Wells, Sara, Wiles, Michael V, Willis, Brandon J, Wood, Joshua A, Wurst, Wolfgang, Xu, Ying, Consortium, International Mouse Phenotyping, Teboul, Lydia, Brown, Steve D M, Murray, Stephen A, Gallegos, Juan J, Green, Jennie R, Bohat, Ritu, Zimmel, Katie, Pereira, Monica, MacMaster, Suzanne, Tondat, Sandra, Wei, Linda, Carroll, Tracy, Bürger, Antje, Cabezas, Jorge, Fan-Lan, Qing, Jacob, Elsa, Creighton, Amie, Castellanos-Penton, Patricia, Danisment, Ozge, Clarke, Shannon, Joeng, Joanna, Kelly, Deborah, To, Christine, Bushell, Wendy, van Bruggen, Rebekah, Gailus-Durner, Valerie, Fuchs, Helmut, Marschall, Susan, Dunst, Stefanie, Romberger, Markus, Rey, Bernhard, Fessele, Sabine, Gormanns, Philipp, Friedel, Roland, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Genotype, Knockout, International Cooperation, [SDV]Life Sciences [q-bio], Mutant, Mutagenesis (molecular biology technique), cytology [Mouse Embryonic Stem Cells], Mouse Mutant Strains, Biology, Genome, Medical and Health Sciences, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Research community, ddc:570, Genetics, Animals, Allele, Gene, Genetic Association Studies, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Internet, metabolism [Mouse Embryonic Stem Cells], Information Dissemination, mutant mouse IMPC, Mouse Embryonic Stem Cells, Biological Sciences, Null allele, Embryonic stem cell, Phenotype, Mutagenesis, Montertondo Mouse Production, Technology Platforms, International Mouse Phenotyping Consortium, Function (biology), 030217 neurology & neurosurgery, Gene Deletion, Developmental Biology
Abstract

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes from targeted embryonic stem cells on the C57BL/6N genetic background. This includes 2,850 null alleles for which no equivalent mutant mouse line exists, 2,987 novel conditional-ready alleles, and 4,433 novel reporter alleles. This nearly triples the number of genes with reporter alleles and almost doubles the number of conditional alleles available to the scientific community. When combined with more than 30 years of community effort, the total mutant allele mouse resource covers more than half of the genome. The extensively validated collection is archived and distributed through public repositories, facilitating availability to the worldwide biomedical research community, and expanding our understanding of gene function and human disease.

Published
2021
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15. Abstract 1575: The landscape of tumor intrinsic immune regulators revealed by genome-wide CRISPR immune screen integrated with comprehensive clinical data analysis

Author

Hou, Jiakai, primary, Wang, Yunfei, additional, Shi, Leilei, additional, Chen, Yuan, additional, Xu, Chunyu, additional, Saeedi, Arash, additional, Pan, Ke, additional, Bohat, Ritu, additional, Egan, Nicholas A., additional, McKenzie, Jodi A., additional, Mbofung, Rina M., additional, Williams, Leila J., additional, Yang, Zhenghuang, additional, Sun, Ming, additional, Liang, Xiaofang, additional, Ahnert, Jordi Rodon, additional, Varadarajan, Navin, additional, Yee, Cassian, additional, Chen, Yiwen, additional, Hwu, Patrick, additional, and Peng, Weiyi, additional

Published
2021
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17. Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

Author

Hou, Jiakai, primary, Wang, Yunfei, additional, Shi, Leilei, additional, Chen, Yuan, additional, Xu, Chunyu, additional, Saeedi, Arash, additional, Pan, Ke, additional, Bohat, Ritu, additional, Egan, Nicholas A., additional, McKenzie, Jodi A., additional, Mbofung, Rina M., additional, Williams, Leila J., additional, Yang, Zhenhuang, additional, Sun, Ming, additional, Liang, Xiaofang, additional, Rodon Ahnert, Jordi, additional, Varadarajan, Navin, additional, Yee, Cassian, additional, Chen, Yiwen, additional, Hwu, Patrick, additional, and Peng, Weiyi, additional

Published
2021
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18. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Haselimashhadi, Hamed, primary, Mason, Jeremy C, additional, Munoz-Fuentes, Violeta, additional, López-Gómez, Federico, additional, Babalola, Kolawole, additional, Acar, Elif F, additional, Kumar, Vivek, additional, White, Jacqui, additional, Flenniken, Ann M, additional, King, Ruairidh, additional, Straiton, Ewan, additional, Seavitt, John Richard, additional, Gaspero, Angelina, additional, Garza, Arturo, additional, Christianson, Audrey E, additional, Hsu, Chih-Wei, additional, Reynolds, Corey L, additional, Lanza, Denise G, additional, Lorenzo, Isabel, additional, Green, Jennie R, additional, Gallegos, Juan J, additional, Bohat, Ritu, additional, Samaco, Rodney C, additional, Veeraragavan, Surabi, additional, Kim, Jong Kyoung, additional, Miller, Gregor, additional, Fuchs, Helmult, additional, Garrett, Lillian, additional, Becker, Lore, additional, Kang, Yeon Kyung, additional, Clary, David, additional, Cho, Soo Young, additional, Tamura, Masaru, additional, Tanaka, Nobuhiko, additional, Soo, Kyung Dong, additional, Bezginov, Alexandr, additional, About, Ghina Bou, additional, Champy, Marie-France, additional, Vasseur, Laurent, additional, Leblanc, Sophie, additional, Meziane, Hamid, additional, Selloum, Mohammed, additional, Reilly, Patrick T, additional, Spielmann, Nadine, additional, Maier, Holger, additional, Gailus-Durner, Valerie, additional, Sorg, Tania, additional, Hiroshi, Masuya, additional, Yuichi, Obata, additional, Heaney, Jason D, additional, Dickinson, Mary E, additional, Wolfgang, Wurst, additional, Tocchini-Valentini, Glauco P, additional, Lloyd, Kevin C Kent, additional, McKerlie, Colin, additional, Seong, Je Kyung, additional, Yann, Herault, additional, de Angelis, Martin Hrabé, additional, Brown, Steve D M, additional, Smedley, Damian, additional, Flicek, Paul, additional, Mallon, Ann-Marie, additional, Parkinson, Helen, additional, and Meehan, Terrence F, additional

Published
2019
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19. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Meehan, Terrence F, Codner, Gemma F, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Loeffler, Jorik, Stewart, Michelle E, Ramirez-Solis, Ramiro, Mason, Jeremy, Bradley, Allan, Skarnes, William C, Steel, Karen P, Maguire, Simon A, Dench, Joshua, Lafont, David, Vancollie, Valerie E, Pearson, Selina A, Gates, Amy S, Sanderson, Mark, Haselimashhadi, Hamed, Shannon, Carl, Anthony, Lauren F E, Sumowski, Maksymilian T, McLaren, Robbie S B, Doe, Brendan, Wardle-Jones, Hannah, Griffiths, Mark N D, Galli, Antonella, Swiatkowska, Agnieszka, Isherwood, Christopher M, Consortium, IMPC, Speak, Anneliese O, Cambridge, Emma L, Wilson, Heather M, Caetano, Susana S, Maguire, Anna Karin B, Adams, David J, Bottomley, Joanna, Ryder, Ed, Gleeson, Diane, Pouilly, Laurent, Hough, Tertius, Rousseau, Stephane, Auburtin, Aurélie, Reilly, Patrick, Ayadi, Abdel, Selloum, Mohammed, Wood, Joshua A, Clary, Dave, Havel, Peter, Tolentino, Todd, Tolentino, Heather, Mallon, Ann-Marie, Schuchbauer, Mike, Pedroia, Sheryl, Trainor, Amanda, Djan, Esi, Pham, Milton, Huynh, Alison, De Vera, Vincent, Seavitt, John, Gallegos, Juan, Garza, Arturo, Wells, Sara, Mangin, Elise, Senderstrom, Joel, Lazo, Iride, Mowrey, Kate, Bohat, Ritu, Samaco, Rodney, Veeraragavan, Surabi, Beeton, Christine, Kalaga, Sowmya, Kelsey, Lois, Santos, Luis, Vukobradovic, Igor, Berberovic, Zorana, Owen, Celeste, Qu, Dawei, Guo, Ruolin, Newbigging, Susan, Morikawa, Lily, Law, Napoleon, Shang, Xueyuan, Feugas, Patricia, Lelliott, Christopher J, Wang, Yanchun, Eskandarian, Mohammad, Zhu, Yingchun, Penton, Patricia, Laurin, Valerie, Clarke, Shannon, Lan, Qing, Sleep, Gillian, Creighton, Amie, Jacob, Elsa, White, Jacqueline K, Danisment, Ozge, Gertsenstein, Marina, Pereira, Monica, MacMaster, Suzanne, Tondat, Sandra, Carroll, Tracy, Cabezas, Jorge, Hunter, Jane, Clark, Greg, Bubshait, Mohammed, Oestereicher, Manuela A, Sorg, Tania, Miller, David, Sohel, Khondoker, Adissu, Hibret, Ganguly, Milan, Bezginov, Alexandr, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Champy, Marie-France, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, La Sala, Gina, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Bower, Lynette R, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D, Wakana, Shigeharu, Suzuki, Tomohiro, Reynolds, Corey L, Tamura, Masaru, Kaneda, Hideki, Furuse, Tamio, Kobayashi, Kimio, Miura, Ikuo, Yamada, Ikuko, Obata, Yuichi, Yoshiki, Atsushi, Ayabe, Shinya, Chambers, J Nicole, Flenniken, Ann M, Chalupsky, Karel, Seisenberger, Claudia, Bürger, Antje, Beig, Joachim, Kühn, Ralf, Hörlein, Andreas, Schick, Joel, Oritz, Oskar, Giesert, Florian, Graw, Jochen, Murray, Stephen A, Ollert, Markus, Schmidt-Weber, Carsten, Stoeger, Tobias, Önder Yildirim, Ali, Eickelberg, Oliver, Klopstock, Thomas, Busch, Dirk H, Bekeredjian, Raffi, Zimmer, Andreas, Jacobsen, Jules O, Nutter, Lauryl M J, Smedley, Damian, Dickinson, Mary E, Benso, Frank, Morse, Iva, Kim, Hyoung-Chin, Lee, Ho, Cho, Soo Young, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Schütt, Christine, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, K. C., McKerlie, Colin, Ravindranath, Aakash Chavan, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Leuchtenberger, Stefanie, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Sharma, Sapna, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, Hrabe de Angelis, Martin, Aguilar-Pimentel, Antonio, Becker, Lore, Treise, Irina, Moreth, Kristin, Garrett, Lillian, Kistler, Martin, Hölter, Sabine M, Zimprich, Annemarie, Marschall, Susan, Amarie, Oana V, Calzada-Wack, Julia, Neff, Frauke, Brachthäuser, Laura, Lengger, Christoph, Stoeger, Claudia, Zapf, Lilly, Willershäuser, Monja, Cho, Yi-Li, da Silva-Buttkus, Patricia, Kraiger, Markus J, Mayer-Kuckuk, Philipp, Gampe, Karen Kristine, Wu, Moya, Conte, Nathalie, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Brommage, Robert, Relac, Mike, Matthews, Peter, Cater, Heather L, Natukunda, Helen P, Cleak, James, Teboul, Lydia M, Clementson-Mobbs, Sharon, Szoke-Kovacs, Zsombor, Walling, Alison P, Johnson, Sara J, Rozman, Jan [0000-0002-8035-8904], Kistler, Martin [0000-0003-0116-7761], Mason, Jeremy [0000-0002-2796-5123], Lelliott, Christopher J [0000-0001-8087-4530], Herault, Yann [0000-0001-7049-6900], Kent Lloyd, KC [0000-0002-5318-4144], McKerlie, Colin [0000-0002-2232-0967], Flicek, Paul [0000-0002-3897-7955], Maier, Holger [0000-0003-2514-8290], Fuchs, Helmut [0000-0002-5143-2677], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Blood Glucose, Candidate gene, Cancer Research, Basal Metabolism/genetics, Gene regulatory network, Obesity/genetics, genetics [Metabolic Diseases], General Physics and Astronomy, Genome-wide association study, Genome, Mice, genetics [Obesity], Triglycerides/metabolism, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Aetiology, lcsh:Science, metabolism [Blood Glucose], Mice, Knockout, Multidisciplinary, genetics [Basal Metabolism], Phenotype, Area Under Curve, Diabetes Mellitus, Type 2/genetics, ddc:500, Technology Platforms, Type 2, metabolism [Triglycerides], Knockout, Science, Computational biology, Biology, genetics [Diabetes Mellitus, Type 2], General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Oxygen Consumption, Metabolic Diseases, Body Weight/genetics, Diabetes Mellitus, Genetics, Animals, Humans, Metabolic Diseases/genetics, Obesity, Gene, Gene knockout, Triglycerides, Oxygen Consumption/genetics, Blood Glucose/metabolism, genetics [Body Weight], Human Genome, Body Weight, Promoter, General Chemistry, genetics [Oxygen Consumption], High-Throughput Screening Assays, 030104 developmental biology, Diabetes Mellitus, Type 2, IMPC Consortium, lcsh:Q, Basal Metabolism, Genome-Wide Association Study
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome., The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

Published
2018
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21. Grape Powder Supplementation Prevents Oxidative Stress–Induced Anxiety-Like Behavior, Memory Impairment, and High Blood Pressure in Rats123

Author

Allam, Farida, Dao, An T., Chugh, Gaurav, Bohat, Ritu, Jafri, Faizan, Patki, Gaurav, Mowrey, Christopher, Asghar, Mohammad, Alkadhi, Karim A., and Salim, Samina

Subjects
Brain Chemistry, Male, Memory Disorders, Nutrition and Disease, Behavior, Animal, Brain-Derived Neurotrophic Factor, Lactoylglutathione Lyase, Polyphenols, Anxiety, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Oxidative Stress, Freeze Drying, Glutathione Reductase, Fruit, Dietary Supplements, Food, Preserved, Hypertension, Animals, Vitis, Cyclic AMP Response Element-Binding Protein, Extracellular Signal-Regulated MAP Kinases, Buthionine Sulfoximine, Calcium-Calmodulin-Dependent Protein Kinase Type 4
Abstract

We examined whether or not grape powder treatment ameliorates oxidative stress–induced anxiety-like behavior, memory impairment, and hypertension in rats. Oxidative stress in Sprague-Dawley rats was produced by using l-buthionine-(S,R)-sulfoximine (BSO). Four groups of rats were used: 1) control (C; injected with vehicle and provided with tap water), 2) grape powder–treated (GP; injected with vehicle and provided for 3 wk with 15 g/L grape powder dissolved in tap water), 3) BSO-treated [injected with BSO (300 mg/kg body weight), i.p. for 7 d and provided with tap water], and 4) BSO plus grape powder–treated (GP+BSO; injected with BSO and provided with grape powder–treated tap water). Anxiety-like behavior was significantly greater in BSO rats compared with C or GP rats (P < 0.05). Grape powder attenuated BSO-induced anxiety-like behavior in GP+BSO rats. BSO rats made significantly more errors in both short- and long-term memory tests compared with C or GP rats (P < 0.05), which was prevented in GP+BSO rats. Systolic and diastolic blood pressure was significantly greater in BSO rats compared with C or GP rats (P < 0.05), whereas grape powder prevented high blood pressure in GP+BSO rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK-1/2) was activated (P < 0.05), whereas levels of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element–binding protein (CREB), and brain-derived neurotrophic factor (BDNF) were significantly less (P < 0.05) in BSO but not in GP+BSO rats compared with C or GP rats. We suggest that by regulating brain ERK-1/2, GLO-1, GSR-1, CAMK-IV, CREB, and BDNF levels, grape powder prevents oxidative stress–induced anxiety, memory impairment, and hypertension in rats.

Published
2013

26. MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors.

Author

Chen S, Hou J, Jaffery R, Guerrero A, Fu R, Shi L, Zheng N, Bohat R, Egan NA, Yu C, Sharif S, Lu Y, He W, Wang S, Gjuka D, Stone EM, Shah PA, Rodon Ahnert J, Chen T, Liu X, Bedford MT, Xu H, and Peng W

Subjects
Animals, Mice, Humans, T-Lymphocytes immunology, T-Lymphocytes drug effects, Cell Line, Tumor, Female, Neoplasms drug therapy, Neoplasms immunology, Isoquinolines, Pyrimidines, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases metabolism, Purine-Nucleoside Phosphorylase antagonists & inhibitors, Purine-Nucleoside Phosphorylase metabolism
Abstract

Background: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer., Methods: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo . Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor., Results: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors., Conclusion: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors., Competing Interests: Competing interests: JRA reports non-financial support and reasonable reimbursement for travel from European Society for Medical Oncology and Loxo Oncology; receiving consulting and travel fees from Ellipses Pharma, Molecular Partners, IONCTURA, Sardona, Mekanistic, Amgen, Merus, MonteRosa, Aadi and Bridgebio (including serving on the scientific advisory board); consulting fees from Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC and Guidepoint, receiving research funding from Blueprint Medicines, Merck Sharp and serving as investigator in clinical trials with Cancer Core Europe, Symphogen, BioAlta, Pfizer, Kelun-Biotech, GlaxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, Merus, Aadi Bioscience, ForeBio, Loxo Oncology, Hutchison MediPharma, Ideaya, Amgen, Tango Therapeutics, Mirati Therapeutics, Linnaeus Therapeutics, MonteRosa, Kinnate, Yingli, Debio, BioTheryX, Storm Therapeutics, Beigene, MapKure, Relay, Novartis, FusionPharma, C4 Therapeutics, Scorpion Therapeutics, Incyte, Fog Pharmaceuticals, Tyra, Nuvectis Pharma. MTB is a co-founder of EpiCypher. No potential conflicts of interest were disclosed by other authors., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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